Program Summary/Abstract Follicular helper T (Tfh) cells provide essential help for B cells and high-affinity antibody production, thereby linking cellular and humoral immunity. While much emphasis has been placed on immune receptors (e.g. ICOS) and transcription factors (e.g. Bcl6) required for Tfh differentiation, how signals are transduced from receptors to transcriptional and biological responses remains poorly defined. Emerging studies reveal nutrient signaling and metabolic reprogramming as fundamental processes underlying the growth and fate decisions of activated lymphocytes. However, many questions remain regarding the specific metabolic pathways important for T cell fate decisions (rather than as a consequence of changes in cellular phenotypes), and how immune signals intersect with nutrient inputs and metabolic programs. For instance, compared with our knowledge on glycolytic or Warburg metabolism, the function and regulation of mitochondrial metabolism are much less clear. We establish that mTOR acts as a key driver of Tfh differentiation by coordinating T cell receptor and ICOS signaling and glucose metabolism. Through unbiased screens, mouse genetic models and systems biology approaches in our preliminary studies, we also revealed crucial roles of nutrient signaling and mitochondrial metabolism in Tfh responses. Our central hypothesis is that the interplay between mTORC1 and nutrient signaling pathways and mitochondrial metabolic programs orchestrates bidirectional metabolic signaling and Tfh differentiation. Specifically, we will (1) identify the mechanisms that integrate nutrient and immune signals in Tfh responses, and (2) establish mitochondrial function and metabolic heterogeneity in Tfh responses. Importantly, despite the emerging interest in immunometabolism, how nutrient signaling and mitochondrial metabolism contribute to T cell function remains poorly understood. Building upon our expertise and innovation that combine genetic and systems biology approaches, we will address fundamental questions of immunometabolism and Tfh biology. Insights gained from this application may significantly impact our understanding of Tfh biology and manifest legitimate therapeutic opportunities.